The present invention relates to compositions and methods for treating cell damage caused by reactive oxygen species in relation to a variety of skin or mucosal membrane disorders. More specifically, the present invention relates to the treatment of skin and mucosal membrane disorders through the topical delivery of compounds that inhibit the production or release of reactive oxygen metabolites.
Reactive oxygen metabolites (ROMs) are often produced by the incomplete reduction of oxygen. The complete reduction of one molecule of O.sub.2 to water is a four-electron process. Oxidative metabolism continually generates partially reduced species of oxygen, which are far more reactive, and hence more toxic than O.sub.2 itself. A one-electron reduction of O.sub.2 yields superoxide ion (O.sub.2); reduction by an additional electron yields hydrogen peroxide (H.sub.2 O.sub.2), and reduction by a third electron yields a hydroxyl radical (OH.), and a hydroxide ion. Nitrous oxide (NO), is another interesting reactive oxygen metabolite, produced through an alternative pathway. Hydroxyl radicals in particular are extremely reactive and represent the most active mutagen derived from ionizing radiation. All of these species are generated and must be converted to less reactive species if the organism is to survive.
Particular cells of the immune system have harnessed the toxic effects of ROMs as an effector mechanism. Professional phagocytes, polymorphonuclear leukocytes (neutrophils, PMN), monocytes, macrophages, and eosinophils function to protect the host in which they reside from infection by seeking out and destroying invading microbes. These phagocytic cells possess a membrane-bound enzyme system that can be activated to produce toxic oxygen radicals in response to a wide variety of stimuli.
The "increased respiration of phagocytosis" (the respiratory burst) was reported and thought to be a result of increased mitochondrial activity providing additional energy for the processes of phagocytosis. It was later shown that a non-mitochondrial enzymatic system produced the increased levels of oxygen metabolites since the respiratory burst continued even in the presence of mitochondrial inhibitors such as cyanide and antimycin A. In 1968, Paul and Sbarra showed clearly that stimulated phagocytes produced hydrogen peroxide and in 1973 Babior and co-workers established that superoxide was a major product of the oxidase. (Paul and Sbarra, Biochim Biophys Acta 156 (1): 168-78 (1968); Babior, et al., J Clin Invest 52(3): 741-4 (1973). It is now generally accepted that the enzyme is membrane bound, exhibits a preference for NADPH (K.sub.m =45 .mu.M) over NADH (K.sub.m =450 .mu.M), and converts oxygen to its one electron-reduced product, superoxide. EQU NADPH+H.sup.+ +2O.sub.2.fwdarw.NADP.sup.+ +2H.sup.+ +2O.sub.2.sup.-
The hydrogen peroxide arises from subsequent dismutation of the superoxide. EQU 2O.sub.2.sup.- +2H.sup.+.fwdarw.H.sub.2 O.sub.2 +O.sub.2.sup.-
The enzyme activity is almost undetectable in resting (unstimulated) phagocytes, but increases dramatically upon stimulation. Patients with the rare genetic disorder chronic granulomatous disease (CGD), have a severe predisposition to chronic recurrent infection. The neutrophils from these patients phagocytose normally but the respiratory burst is absent and NADPH oxidase activity (and radical production) is undetectable, indicating that the oxidase and its product, the reactive oxygen metabolites, have an important bactericidal function.
Neutrophils and macrophages produce oxidizing agents to break through the protective coats or other factors that protect phagocytosed bacteria. The large quantities of superoxide, hydrogen peroxide, and hydroxyl ions are all lethal to most bacteria, even when found in very small quantities.
While there are beneficial effects of these oxygen metabolites, it is clear that inappropriate production of oxygen metabolites can result in severely deleterious effects. A number of these deleterious effects manifest themselves in the dermal tissues and mucosal membranes of the host. For example, a variety of skin disorders including herpes simplex infections, and chemical and heat induced skin lesions can be exacerbated by unwanted concentrations of reactive oxygen metabolites. Effective compositions and methods to reduce and minimize the production and release of ROMs in patients suffering from a variety of disparate disorders would be a great boon to medicine and serve to reduce and eliminate a substantial amount of human suffering.
Topically administered salves, balms and other such medicaments are well known in the art. The application of mud or plant extracts such as aloe vera are just two examples of such medicaments. For a discussion of aloe vera, see U.S. Pat. No. 4,857,328, which is hereby incorporated by reference. The use of two different histamine derivatives as topically administered skin medicaments has also been discussed previously. The first may be found in a series of U.S. Patents to Jack et al., which disclose the use of a pharmaceutical composition of water, water soluble vinyl polymer gel, an amine alcohol dispersant and 1H-imidazole-4-ethanamine phosphate to treat certain skin disorders. See U.S. Pat. Nos. 5,294,440; 5,679,337; and 5,716,610. The second is found in U.S. Pat. No. 5,792,784, that discloses a pseudo-dipeptide product obtained by coupling histamine or a methyl-substituted histamine and an amino acid.